The discovery of microRNAs (miRNAs) in the last decade, and the realization of their growing importance in carcinogenesis and cancer prognosis through regulation of transcription of oncogenes and tumor suppressor genes (TSGs), has led to an era of excitement of discovery regarding these small molecules. Although it is known that there is widespread misexpression of miRNAs in many cancer tissues, including breast cancer, little is known regarding how inherited variability in miRNA genes and their responsive elements in target genes may predispose to cancer. As a consequence of the particular way in which miRNAs function - by targeting a number of functionally important protein-coding genes, such as oncogenes and TSGs - genetic variations in miRNA genes and their responsive elements in target genes could be important in cancer predisposition. Inherited variability in miRNAs may be extremely relevant for breast cancer, as family history has consistently been regarded as a major risk factor for breast cancer. Germ-line mutations in the currently known high-risk breast cancer genes (such as BRCA1/2, etc) are common in familial breast cancer, but they can explain at best 20-25% of the overall excess familial risk, suggesting the presence of other unidentified predisposition genes, which confer susceptibility to breast cancer. Considerable efforts have been made to discover breast susceptibility genes, however so far few have been identified. The dilemma might be due to the fact that susceptibility alleles reside in protein non-encoding genes, such as miRNAs, or miRNA responsive elements at 3'UTR of the target genes, which are traditionally overlooked in genetic screening. We propose a study by utilizing valuable resource from Cooperative Familial Registry for Breast Cancer Studies (CFRBCS) to screen genetic variants in selected miRNA genes and their responsive elements in target genes in hereditary breast cancer families, to assess the genetic susceptibility of these genetic variants in the development of hereditary and/or sporadic breast cancer, and to functionally characterize these genetic variants. We hypothesize that genetic variations in miRNA genes and their responsive elements in target genes alter various biological processes by influencing the biological functions of miRNAs, and thereby modify genetic predisposition to breast cancer. Because this research is nested within the CFRBCS, the objectives can be addressed in a timely and cost effective manner. This innovative and important area has not been investigated yet. The proposed research will help us to elucidate the biological significance of miRNA in breast cancer, explore the functional significance of these inherited variations, and establish a solid foundation for understanding the role of miRNA in breast cancer predisposition. From a clinical perspective, the long-term application of this information to risk assessment and thus to the prevention and early detection of breast cancer in families as well as population will be significant. PUBLIC HEALTH RELEVANCE: The proposed research will help us to elucidate the biological significance of miRNA in breast cancer, explore the functional significance of these inherited variations, and establish a solid foundation for understanding the role of miRNA in breast cancer predisposition. From a clinical perspective, the long-term application of this information to risk assessment and thus to the prevention and early detection of breast cancer in families as well as population will be significant.